Base-specific mutational intolerance near splice sites clarifies the role of nonessential splice nucleotides

Variation in RNA splicing (i.e., alternative splicing) plays an important role in many diseases. Variants near 5' and 3' splice sites often affect splicing, but the effects of these variants on splicing and disease have not been fully characterized beyond the two "essential" splice nucleotides flanking each exon. Here we provide quantitative measurements of tolerance to mutational disruptions by position and reference allele-alternative allele combinations. We show that certain reference alleles are particularly sensitive to mutations, regardless of the alternative alleles into which they are mutated. Using public RNA-seq data, we demonstrate that individuals carrying such variants have significantly lower levels of the correctly spliced transcript, compared to individuals without them, and confirm that these specific substitutions are highly enriched for known Mendelian mutations. Our results propose a more refined definition of the "splice region" and offer a new way to prioritize and provide functional interpretation of variants identified in diagnostic sequencing and association studies.Peer reviewe

Reply to : On powerful GWAS in admixed populations

Non peer reviewe

A large population-based investigation into the genetics of susceptibility to gastrointestinal infections and the link between gastrointestinal infections and mental illness.

Gastrointestinal infections can be life threatening, but not much is known about the host's genetic contribution to susceptibility to gastrointestinal infections or the latter's association with psychiatric disorders. We utilized iPSYCH, a genotyped population-based sample of individuals born between 1981 and 2005 comprising 65,534 unrelated Danish individuals (45,889 diagnosed with mental disorders and 19,645 controls from a random population sample) in which all individuals were linked utilizing nationwide population-based registers to estimate the genetic contribution to susceptibility to gastrointestinal infections, identify genetic variants associated with gastrointestinal infections, and examine the link between gastrointestinal infections and psychiatric and neurodevelopmental disorders. The SNP heritability of susceptibility to gastrointestinal infections ranged from 3.7% to 6.4% on the liability scale. Significant correlations were found between gastrointestinal infections and the combined group of mental disorders (OR = 2.09; 95% CI: 1.82-2.4, P = 1.87 × 10-25). Correlations with autism spectrum disorder, attention deficit hyperactivity disorder, and depression were also significant. We identified a genome-wide significant locus associated with susceptibility to gastrointestinal infections (OR = 1.13; 95% CI: 1.08-1.18, P = 2.9 × 10-8), where the top SNP was an eQTL for the ABO gene. The risk allele was associated with reduced ABO expression, providing, for the first time, genetic evidence to support previous studies linking the O blood group to gastrointestinal infections. This study also highlights the importance of integrative work in genetics, psychiatry, infection, and epidemiology on the road to translational medicine

SAIGE-GENE plus improves the efficiency and accuracy of set-based rare variant association tests

Several biobanks, including UK Biobank (UKBB), are generating large-scale sequencing data. An existing method, SAIGE-GENE, performs well when testing variants with minor allele frequency (MAF) SAIGE-GENE+ performs set-based rare variant association tests with improved type 1 error control and computational efficiency by collapsing ultra-rare variants and conducting multiple tests corresponding to different minor allele frequency cutoffs and annotations.Peer reviewe

A review of the Pteropus rufus (É. Geoffroy, 1803) colonies within the Tolagnaro region of southeast Madagascar – an assessment of neoteric threats and conservation condition

We surveyed 10 Pteropus rufus roost sites within the southeastern Anosy Region of Madagascar to provide an update on the areas’ known flying fox population and its conservation status. We report on two new colonies from Manambaro and Mandena and provide an account of the colonies first reported and last assessed in 2006. Currently only a solitary roost site receives any formal protection (Berenty) whereas further two colonies rely solely on taboo ‘fady’ for their security. We found that only two colonies now support an increased number of bats compared with a decade ago, whilst a further two colonies have been either displaced or disturbed and could no longer be found. A single colony appears to have declined significantly whereas a further three colonies appear to have remained static. In light of a decree that has imposed a specific hunting season for fruit bats, we hope that this census can provide a baseline for future population monitoring and contribute towards the assessment of the effectiveness of the legislation

Polygenic risk heterogeneity among focal epilepsies

Focal epilepsy (FE) is clinically highly heterogeneous. It has been shown recently that not only rare but also a subset of common genetic variants confer risk for FE. The relatively modest power of genetic studies in FE suggests a high genetic heterogeneity of FE when grouped as one disorder. We hypothesize that the clinical heterogeneity of FE is correlated with genetic heterogeneity on a common risk variant level. To test the hypothesis, we used an FE polygenic risk score "FE-PRS" that combines small effect sizes of thousands of common variants from the largest FE-GWAS (genome-wide association study) into a single measure. We grouped 414 individuals with FE according to common clinical features into subgroups, either by one feature at a time or by all features combined in a cluster analysis. We examined their association with FE-PRS compared to 20 435 matched population controls and observed heterogeneous FE-PRS burden among the subgroups. The highest phenotypic variance explained by FE-PRS was identified in a cluster analysis-defined FE subgroup where all individuals had unknown etiologies and psychiatric comorbidities, and the majority had early onset seizures. Our results indicate that genetic factors associated with FE have differential burden among FE subtypes. Future studies using better-powered FE-PRS might have clinical utility.Peer reviewe

Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia : a genetic and functional study

Objective To study genetic variants and their function within genes coding for complement receptors in pre-eclampsia. Design A case-control study. Setting Pre-eclampsia is a common vascular disease of pregnancy. The clearance of placenta-derived material is one of the functions of the complement system in pregnancy. Population We genotyped 500 women with pre-eclamptic pregnancies and 190 pregnant women without pre-eclampsia, as controls, from the FINNPEC cohort, and 122 women with pre-eclamptic pregnancies and 1905 controls from the national FINRISK cohort. Methods The functional consequences of genotypes discovered by targeted exomic sequencing were explored by analysing the binding of the main ligand iC3b to mutated CR3 or CR4, which were transiently expressed on the surface of COS-1 cells. Main outcome measures Allele frequencies were compared between pre-eclamptic pregnancies and controls in genetic studies. The functional consequences of selected variants were measured by binding assays. Results The most significantly pre-eclampsia-linked CR3 variant M441K (P = 4.27E-4, OR = 1.401, 95% CI = 1.167-1.682) displayed a trend of increased adhesion to iC3b (P = 0.051). The CR4 variant A251T was found to enhance the adhesion of CR4 to iC3b, whereas W48R resulted in a decrease of the binding of CR4 to iC3b. Conclusions Results suggest that changes in complement-facilitated phagocytosis are associated with pre-eclampsia. Further studies are needed to ascertain whether aberrant CR3 and CR4 activity leads to altered pro- and anti-inflammatory cytokine responses in individuals carrying the associated variants, and the role of these receptors in pre-eclampsia pathogenesis. Tweetable abstract Genetic variants of complement receptors CR3 and CR4 have functional consequences that are associated with pre-eclampsia.Peer reviewe

Mapping and characterization of structural variation in 17,795 human genomes

Structural variants in more than 17,000 human genomes are mapped and characterized using whole-genome sequencing, showing how this type of variation contributes to rare deleterious coding and noncoding alleles. A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline(1)to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.Peer reviewe

Young stars and non-stellar emission in the aligned radio galaxy 3C 256

We present ground-based images of the z=1.824 radio galaxy 3C 256 in the standard BVRIJHK filters and an interference filter centered at 8800A, a Hubble Space Telescope image in a filter dominated by Ly-alpha emission (F336W), and spectra covering rest-frame wavelengths from Ly-alpha to [O III] 5007. Together with published polarimetry observations, we use these to decompose the overall spectral energy distribution into nebular continuum emission, scattered quasar light, and stellar emission. The nebular continuum and scattered light together comprise half (one third) of the V-band (K-band) light within a 4-arcsec aperture, and are responsible for the strong alignment between the optical/near-infrared light and the radio emission. The stellar emission is dominated by a population estimated to be 100-200 Myr old (assuming a Salpeter IMF), and formed in a short burst with a peak star formation rate of 1-4x10^3 Msun/yr. The total stellar mass is estimated to be no more than 2x10^{11} Msun, which is far less than other luminous radio galaxies at similar redshifts, and suggests that 3C 256 will undergo further star formation or mergers.Comment: 35 pages including 10 figures; to appear in Nov 10 Ap

Care of elderly in Portugal: Official data and scientific and professional challenges

First published online: 10 August 2019The world has never been so active in approaching human needs and human rights. As the population has become older, new kind of pressures has been made over health and protective services, as well as on research targeted to older adults. This chapter presents the scientific and practical developments in the field of elder mistreatment in Portugal. An overview of the scientific trends in Portuguese research is presented. National research on elder mistreatment has been increasing slowly. The current national scenery is focused on prevalence data and identifying risk and vulnerabilities. This chapter will also discuss the support structures available for mistreated older adults in Portugal, namely the current legal framework and the institutions/entities that offer aid to the victims. Legally, elder mistreatment in Portugal is no different from domestic violence, though some legislative advances have been seen in abandonment. Some structures have been developed over the years to offer aid to older adults, from special programs in the police to private institutions, passing by government supported initiatives.This study was conducted at Psychology Research Centre (UID/PSI/01662/2013), University of Minho, and supported by the Portuguese Foundation for Science and Technology and the Portuguese Ministry of Science, Technology and Higher Education through national funds and co-financed by FEDER through COMPETE2020 under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007653). The first author was funded by a scholarship from the Portuguese Foundations for Science and Technology - FCT - (PD/BD/105965/2014